This invention relates to pharmaceutical compositions comprising xcex23 adrenergic agonists including (4-(2-(2-(6-aminopyridin-3-yl)-2(R)-hydroxyethylamino)ethoxy)phenyl)acetic acid and growth hormone or growth hormone secretagogues, prodrugs thereof or pharmaceutically acceptable salts of said compounds or said prodrugs. These compositions have utility, inter alia, in the treatment of obesity, diabetes, hypertension and frailty in animals and particularly in humans. Accordingly, this invention also relates to methods of using such compositions for the treatment of obesity, diabetes, hypertension and frailty in animals, particularly humans.
Compounds of the Formula I 
are disclosed in commonly assigned International Patent Application Numbers WO 96/35671 and WO96/35670, each designating, inter alia, the United States, as xcex23 adrenergic agonists having utility in treating obesity, the disclosure of which is incorporated herein by reference. The various substituents of the compound of Formula I are as defined in those patent applications. Within the scope of that disclosure is 4-(2-(2-(6-aminopyridin-3-yl)-2(R)-hydroxyethylamino)ethoxy)phenyl)acetic acid, the compound of Formula II, 
xcex2-Adrenergic agents have been categorized into xcex21, xcex22, and xcex23 subtypes. Agonists of xcex2-receptors promote the activation of adenyl cyclase. Activation of xcex21 receptors invokes increases in heart rate. Activation of xcex22 receptors induces relaxation of smooth muscle tissue which produces a drop in blood pressure and the onset of skeletal muscle tremors. Activation of xcex23 receptors is known to stimulate lipolysis, which is the breakdown of adipose tissue triglycerides to glycerol and fatty acids. Activation of xcex23 receptors also stimulates the metabolic rate, thereby increasing energy expenditure. Accordingly, activation of xcex23 receptors promotes the loss of fat mass. Compounds that stimulate xcex23 receptors are therefore useful as anti-obesity agents.
International Patent Application Publication No. WO 97/16189, designating, inter alia, the United States, the disclosure of which is incorporated herein by reference, discloses the use of selective xcex23 receptor agonists in combination with compounds which modify eating behavior for the treatment of obesity.
International Patent Application Publication Number WO 96/24369, designating, inter alia, the United States, which is incorporated herein by reference, discloses growth hormone secretagogues of the Formula III 
wherein the variables are as defined in WO96/24369.
Commonly assigned U.S. Provisional Application No. 60/050764, filed Jun. 25, 1997, which is incorporated herein by reference, discloses growth hormone secretagogues of the Formula IV 
This invention is directed to pharmaceutical compositions comprising a xcex23 adrenergic agonist, a growth hormone secretagogue or growth hormone and a pharmaceutically acceptable carrier or diluent.
A group of preferred compositions, designated the A Group, are those pharmaceutical compositions as disclosed in the immediately preceding paragraph wherein said xcex23 adrenergic agonist is a compound of the Formula I: 
wherein:
R1g, R2g, R4g, and R5g are independently hydrogen or (C1-C6)alkyl;
R3g, R6g and R7g are independently hydrogen, halogen, (C1-C6)alkyl, nitro, cyano, trifluoromethyl, SO2R8g, SO2NR9gR10g, NR9gR10g, COR11g, CO2R9g, (C1-C6)alkoxy, NR9gSO2R8g, NR9gCOR11g, NR9gCO2R9g or OR9g;
R8g is independently (C1-C6)alkyl or (C1-C6)alkoxy(C1-C6)alkyl;
R9g and R10g are independently hydrogen, (C1-C6)alkyl, cycloalkyl(C3-C8), or (C1-C6)alkoxy(C1-C6)alkyl;
R11g is independently hydrogen, (C1-C6)alkyl, NR9gR10g, (C3-C8)cycloalkyl, or (C1-C6)alkoxy(C1-C6)alkyl;
W1 is N, CH, or, when R3g is bonded to W1, CR3g wherein R3g can be any of the values listed above for R3g in addition to H;
W2 and W3 are independently a direct link, oxygen, sulfur, or NR1g wherein R1g is as defined above;
W4 is (CH2)yOR9g, (CH2)zCO2R11g, (CH2)zCOR11g, (CH2)zSO2NR9gR10g, (CH2)zxe2x80x94NR9gSO2R8g, (CH2)zP(O)(OR1g)(OR2g), (CH2)zxe2x80x94Oxe2x80x94(CH2)yCO2R11g, (CH2)nxe2x80x94Oxe2x80x94(CH2)yCOR11g, (CH2)zxe2x80x94Oxe2x80x94(CH2)yP(O)(OR1g)(OR2g), (CH2)zxe2x80x94Oxe2x80x94(CH2)ySO2NR9gR10g, or (CH2)zxe2x80x94Oxe2x80x94(CH2)yNR9gSO2R8g wherein R1g, R2g, R8g, R9g, R10g, and R11g are as defined above;
y is 1 to 6;
z is 0 to 6, provided that if W3 is O or S, z is not 0;
pharmaceutically acceptable prodrugs of said compounds; and
pharmaceutically acceptable salts of said compounds and said prodrugs.
A group of compositions which is preferred within the A Group are those compositions, designated Group B, wherein said xcex23 adrenergic agonist is (4-(2-(2-(6-aminopyridin-3-yl)-2(R)-hydroxyethylamino)ethoxy)phenyl)acetic acid, a prodrug thereof, or a pharmaceutically acceptable salt of said xcex23 adrenergic agonist or said prodrug.
A more preferred group of compositions within the B Group are those compositions comprising growth hormone.
Another more preferred group of compositions within the B Group are those compositions comprising (N-(1(R)-((1,2-dihydro-1-methanesulfonyl-spiro(3H-indole-3,4xe2x80x2-piperidin)-1xe2x80x2-yl)carbonyl)-2-(phenylmethyloxy)ethyl)-2-amino-2-methylpropanamide.
Yet another more preferred group of compositions within the B Group are those compositions, designated Group C, wherein said growth hormone secretagogue is a compound of the Formula IV: 
or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, wherein
HET is a heterocyclic moiety selected from the group consisting of 
d is 0, 1 or 2;
e is 1 or 2;
f is 0 or 1;
n and w are 0, 1 or 2, provided that n and w cannot both be 0 at the same time;
Y2 is oxygen or sulfur;
A is a divalent radical, where the left hand side of the radical as shown below is connected to Cxe2x80x3 and the right hand side of the radical as shown below is connected to Cxe2x80x2, selected from the group consisting of
xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94S(O)2xe2x80x94NR2xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NR2C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NR2xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94NR2xe2x80x94C(O)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94S(O)2xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94Oxe2x80x94C(R9R10)xe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94C(O)xe2x80x94NR2xe2x80x94C(O)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NR2xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94S(O)2xe2x80x94NR2xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94NR2xe2x80x94C(O)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94NR2xe2x80x94S(O)2xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94C(O)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94NR2xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(R9R10)xe2x80x94Oxe2x80x94C(O)xe2x80x94NR2, xe2x80x94C(R9R10)xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94Oxe2x80x94C(R9R10)xe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94C(R9R10)xe2x80x94, xe2x80x94NR2xe2x80x94S(O)2xe2x80x94NR2xe2x80x94C(R9R10)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94NR2xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(O)xe2x80x94Nxe2x95x90C(R11)xe2x80x94NR2xe2x80x94, xe2x80x94C(O)xe2x80x94NR2xe2x80x94C(R11)xe2x95x90Nxe2x80x94, xe2x80x94C(R9R10)xe2x80x94NR12xe2x80x94C(R9R10)xe2x80x94, xe2x80x94NR12xe2x80x94C(R9R10)xe2x80x94, xe2x80x94NR12xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94NR2xe2x80x94C(R11)xe2x95x90Nxe2x80x94C(O)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94N(R12)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94NR12xe2x80x94, xe2x80x94Nxe2x95x90C(R11)xe2x80x94NR2xe2x80x94C(O)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94NR2xe2x80x94S(O)2xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94S(O)2xe2x80x94NR2xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(R9R10)xe2x80x94S(O)2xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94S(O)2xe2x80x94, xe2x80x94Oxe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94Oxe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(O)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(O)xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94 and xe2x80x94C(R9R10)xe2x80x94NR2xe2x80x94S(O)2xe2x80x94NR2xe2x80x94;
Q is a covalent bond or CH2;
W is CH or N;
X is CR9R10, Cxe2x95x90CH2 or Cxe2x95x90O;
Y is CR9R10, O or NR2;
Z is Cxe2x95x90O, Cxe2x95x90S or S(O)2;
G1 is hydrogen, halo, hydroxy, nitro, amino, cyano, phenyl, carboxyl, xe2x80x94CONH2, xe2x80x94(C1-C4)alkyl optionally independently substituted with one or more phenyl, one or more halogens or one or more hydroxy groups, xe2x80x94(C1-C4)alkoxy optionally independently substituted with one or more phenyl, one or more halogens or one or more hydroxy groups, xe2x80x94(C1-C4)alkylthio, phenoxy, xe2x80x94COO(C1-C4)alkyl, N,N-di-(C1-C4)alkylamino, xe2x80x94(C2-C6)alkenyl optionally independently substituted with one or more phenyl, one or more halogens or one or more hydroxy groups, xe2x80x94(C2-C6)alkynyl optionally independently substituted with one or more phenyl, one or more halogens or one or more hydroxy groups, xe2x80x94(C3-C6)cycloalkyl optionally independently substituted with one or more (C1-C4)alkyl groups, one or more halogens or one or more hydroxy groups, xe2x80x94(C1-C4)alkylamino carbonyl or di-(C1-C4)alkylamino carbonyl;
G2 and G3 are each independently selected from the group consisting of hydrogen, halo, hydroxy, xe2x80x94(C1-C4)alkyl optionally independently substituted with one to three halo groups and xe2x80x94(C1-C4)alkoxy optionally independently substituted with one to three halo groups;
R1 is hydrogen, xe2x80x94CN, xe2x80x94(CH2)qN(X6)C(O)X6, xe2x80x94(CH2)qN(X6)C(O)(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)S(O)2(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)S(O)2X6, xe2x80x94(CH2)qN(X6)C(O)N(X6)(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)C(O)N(X6)(X6), xe2x80x94(CH2)qC(O)N(X6)(X6), xe2x80x94(CH2)qC(O)N(X6)(CH2)txe2x80x94A1, xe2x80x94(CH2)qC(O)OX6, xe2x80x94(CH2)qC(O)O(CH2)txe2x80x94A1, xe2x80x94(CH2)qOX6, xe2x80x94(CH2)qOC(O)X6, xe2x80x94(CH2)qOC(O)(CH2)txe2x80x94A1, xe2x80x94(CH2)qOC(O)N(X6)(CH2)txe2x80x94A1, xe2x80x94(CH2)qOC(O)N(X6)(X6), xe2x80x94(CH2)qC(O)X6, xe2x80x94(CH2)qC(O)(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)C(O)OX6, xe2x80x94(CH2)qN(X6)S(O)2N(X6)(X6), xe2x80x94(CH2)qS(O)mX6, xe2x80x94(CH2)qS(O)m(CH2)txe2x80x94A1, xe2x80x94(C1-C10)alkyl, xe2x80x94(CH2)txe2x80x94A1, xe2x80x94(CH2)qxe2x80x94(C3-C7)cycloalkyl, xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(C1-C6)alkyl, xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(CH2)txe2x80x94A1 or xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(CH2)txe2x80x94(C3-C7)cycloalkyl;
where the alkyl and cycloalkyl groups in the definition of R1 are optionally substituted with (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, carboxyl, xe2x80x94CONH2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94CO2(C1-C4)alkyl ester, 1H-tetrazol-5-yl or 1, 2 or 3 fluoro groups;
Y1 is O, S(O)m, xe2x80x94C(O)NX6xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94N(X6)C(O)xe2x80x94, xe2x80x94C(O)NX6xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)N(X6)xe2x80x94 or xe2x80x94OC(O)xe2x80x94;
q is 0, 1, 2, 3 or 4;
t is O, 1, 2 or 3;
said xe2x80x94(CH2)q group and xe2x80x94(CH2)t group in the definition of R1 are optionally independently substituted with hydroxy, (C1-C4)alkoxy, carboxyl, xe2x80x94CONH2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94CO2(C1-C4)alkyl ester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro groups or 1 or 2 (C1-C4)alkyl groups;
R1A is selected from the group consisting of hydrogen, F, Cl, Br, I, (C1-C6)alkyl, phenyl(C1-C3)alkyl, pyridyl(C1-C3)alkyl, thiazolyl(C1-C3)alkyl and thienyl(C1-C3)alkyl, provided that R1A is not F, Cl, Br or I when a heteroatom is vicinal to Cxe2x80x3;
R2 is hydrogen, (C1-C8)alkyl, xe2x80x94(C0-C3)alkyl-(C3-C8)cycloalkyl, xe2x80x94(C1-C4)alkyl-A1 or A1;
where the alkyl groups and the cycloalkyl groups in the definition of R2 are optionally substituted with hydroxy, xe2x80x94C(O)OX6, xe2x80x94C(O)N(X6)(X6), xe2x80x94N(X6)(X6), xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)A1, xe2x80x94C(O)(X6), CF3, CN or 1, 2 or 3 independently selected halo groups;
R3 is selected from the group consisting of A1, (C1-C10)alkyl, xe2x80x94(C1-C6)alkyl-A1, xe2x80x94(C1-C6)alkyl-(C3-C7)cycloalkyl, xe2x80x94(C1-C5)alkyl-X1xe2x80x94(C1-C5)alkyl, xe2x80x94(C1-C5)alkyl-X1xe2x80x94(C0-C5)alkyl-A1 and xe2x80x94(C1-C5)alkyl-X1xe2x80x94(C1-C5)alkyl-(C3-C7)cycloalkyl;
where the alkyl groups in the definition of R3 are optionally substituted with xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)OX3, 1, 2, 3, 4 or 5 independently selected halo groups or 1, 2 or 3 independently selected xe2x80x94OX3 groups;
X1 is O, S(O)m, xe2x80x94N(X2)C(O)xe2x80x94, xe2x80x94C(O)N(X2)xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94CX2xe2x95x90CX2xe2x80x94, xe2x80x94N(X2)C(O)Oxe2x80x94, xe2x80x94OC(O)N(X2)xe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94;
R4 is hydrogen, (C1-C6)alkyl or (C3-C7)cycloalkyl, or R4 is taken together with R3 and the carbon atom to which they are attached and form (C5-C7)cycloalkyl, (C5-C7)cycloalkenyl, a partially saturated or fully saturated 4- to 8-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, or is a bicyclic ring system consisting of a partially saturated or fully saturated 5- or 6-membered ring, fused to a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
X4 is hydrogen or (C1-C6)alkyl or X4 is taken together with R4 and the nitrogen atom to which X4 is attached and the carbon atom to which R4 is attached and form a five to seven membered ring;
R6 is a bond or is 
where a and b are each independently 0, 1, 2 or 3;
X5 and X5a are each independently selected from the group consisting of hydrogen, CF3, A1 and optionally substituted (C1-C6)alkyl;
the optionally substituted (C1-C6)alkyl in the definition of X5 and X5a is optionally substituted with a substituent selected from the group consisting of A1, OX2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)OX2, (C3-C7)cycloalkyl, xe2x80x94N(X2)(X2) and xe2x80x94C(O)N(X2)(X2);
or the carbon bearing X5 or X5a forms one or two alkylene bridges with the nitrogen atom bearing R7 and R8 wherein each alkylene bridge contains 1 to 5 carbon atoms, provided that when one alkylene bridge is formed then only one of X5 or X5a is on the carbon atom and only one of R7 or R8 is on the nitrogen atom and further provided that when two alkylene bridges are formed then X5 and X5a cannot be on the carbon atom and R7 and R8 cannot be on the nitrogen atom;
or X5 is taken together with X5a and the carbon atom to which they are attached and form a partially saturated or fully saturated 3- to 7-membered ring, or a partially saturated or fully saturated 4- to 8-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen;
or X5 is taken together with X5a and the carbon atom to which they are attached and form a bicyclic ring system consisting of a partially saturated or fully saturated 5- or 6-membered ring, optionally having 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
Z1 is a bond, O or Nxe2x80x94X2, provided that when a and b are both 0 then Z1 is not Nxe2x80x94X2 or O;
R7 and R8 are each independently hydrogen or optionally substituted (C1-C6)alkyl;
where the optionally substituted (C1-C6)alkyl in the definition of R7 and R8 is optionally independently substituted with A1, xe2x80x94C(O)Oxe2x80x94(C1-C6)alkyl, xe2x80x94S(O)m(C1-C6)alkyl, 1 to 5 halo groups, 1 to 3 hydroxy groups, 1 to 3 xe2x80x94Oxe2x80x94C(O)(C1-C10)alkyl groups or 1 to 3 (C1-C6)alkoxy groups; or
R7 and R8 can be taken together to form xe2x80x94(CH2)rxe2x80x94Lxe2x80x94(CH2)rxe2x80x94;
where L is C(X2)(X2), S(O)m or N(X2);
R9 and R10 are each independently selected from the group consisting of hydrogen, fluoro, hydroxy and (C1-C5)alkyl optionally independently substituted with 1-5 halo groups;
R11 is selected from the group consisting of (C1-C5)alkyl and phenyl optionally substituted with 1-3 substitutents each independently selected from the group consisting of (C1-C5)alkyl, halo and (C1-C5)alkoxy;
R12 is selected from the group consisting of (C1-C5)alkylsulfonyl, (C1-C5)alkanoyl and (C1-C5)alkyl where the alkyl portion is optionally independently substituted by 1-5 halo groups;
A1 for each occurrence is independently selected from the group consisting of (C5-C7)cycloalkenyl, phenyl, a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen and a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
A1 for each occurrence is independently optionally substituted, on one or optionally both rings if A1 is a bicyclic ring system, with up to three substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF3, OCF2H, CF3, CH3, OCH3, xe2x80x94OX6, xe2x80x94C(O)N(X6)(X6), xe2x80x94C(O)OX6, oxo, (C1-C6)alkyl, nitro, cyano, benzyl, xe2x80x94S(O)m(C1-C6)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, xe2x80x94N(X6)(X6), xe2x80x94N(X6)C(O)(X6), xe2x80x94S(O)2N(X6)(X6), xe2x80x94N(X6)S(O)2-phenyl, xe2x80x94N(X6)S(O)2X6, xe2x80x94CONX11X12, xe2x80x94S(O)2NX11X12, xe2x80x94NX6S(O)2X12, xe2x80x94NX6CONX11X12, xe2x80x94NX6S(O)2NX11X12, xe2x80x94NX6C(O)X12, imidazoyl, thiazolyl and tetrazolyl, provided that if A1 is optionally substituted with methylenedioxy then it can only be substituted with one methylenedioxy;
where X11 is hydrogen or optionally substituted (C1-C6)alkyl;
the optionally substituted (C1-C6)alkyl defined for X11 is optionally independently substituted with phenyl, phenoxy, (C1-C6)alkoxycarbonyl, xe2x80x94S(O)m(C1-C6)alkyl, 1 to 5 halo groups, 1 to 3 hydroxy groups, 1 to 3 (C1-C10)alkanoyloxy groups or 1 to 3 (C1-C6)alkoxy groups;
X12 is hydrogen, (C1-C6)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X12 is not hydrogen, the X12 group is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH3, OCH3, OCF3 and CF3;
or X11 and X12 are taken together to form xe2x80x94(CH2)rxe2x80x94L1xe2x80x94(CH2)rxe2x80x94;
L1 is C(X2)(X2), O, S(O)m or N(X2);
r for each occurrence is independently 1, 2 or 3;
X2 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl or optionally substituted (C3-C7)cycloalkyl, where the optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X2 are optionally independently substituted with xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)OX3, 1 to 5 halo groups or 1-3 OX3 groups;
X3 for each occurrence is independently hydrogen or (C1-C6)alkyl;
X6 for each occurrence is independently hydrogen, optionally substituted (C1-C7)alkyl, (C2-C6)halogenated alkyl, optionally substituted (C3-C6)cycloalkyl, (C3-C7)-halogenated cycloalkyl, where optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X6 is optionally independently mono- or di-substituted with (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, carboxyl, CONH2, xe2x80x94S(O)m(C1-C6)alkyl, carboxylate (C1-C4)alkyl ester or 1H-tetrazol-5-yl; or
when there are two X6 groups on one atom and both X6 are independently (C1-C6)alkyl, the two (C1-C6)alkyl groups may be optionally joined and, together with the atom to which the two X6 groups are attached, form a 4- to 9-membered ring optionally having oxygen, sulfur or NX7 as a ring member;
X7 is hydrogen or (C1-C6)alkyl optionally substituted with hydroxy;
m for each occurrence is independently 0, 1 or 2.
A preferred group within the C Group are those compositions, designated Group D, wherein said growth hormone secretagogue is 2-amino-N-(2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide, a prodrug thereof or a pharmaceutically acceptable salt of said growth hormone secretagogue or said prodrug.
A more preferred group within the D Group are those compositions comprising (4-(2-(2-(6-aminopyridin-3-yl)-2(R)-hydroxyethylamino)ethoxy)phenyl)acetic acid and 2-amino-N-(2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide, a prodrug of either entity or a pharmaceutically acceptable salt of either entity.
Another preferred group within the C Group are those compositions, designated Group E, wherein said growth hormone secretagogue is 2-amino-N-(1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-yl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-ethyl)-2-methylpropionamide, a prodrug thereof or a pharmaceutically acceptable salt of said growth hormone secretagogue or said prodrug.
A more preferred group within the E Group are those compositions comprising (4-(2-(2-(6-aminopyridin-3-yl)-2(R)-hydroxyethylamino)ethoxy)phenyl)acetic acid and 2-amino-N-(1-(R)-(2,4-difluorobenzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-yl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide, a prodrug of either entity or a pharmaceutically acceptable salt of either entity.
Yet another preferred group within the C Group are those compositions, designated Group F, wherein said growth hormone secretagogue is 2-amino-N-{1(R)-benzyloxymethyl-2-[1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide, a prodrug thereof or a pharmaceutically acceptable salt of said growth hormone secretagogue or said prodrug.
A more preferred group within the F Group are those compositions comprising (4-(2-(2-(6-aminopyridin-3-yl)-2(R)-hydroxyethylamino)ethoxy)phenyl)acetic acid and 2-amino-N-{(R)-benzyloxymethyl-2-[1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide, a prodrug of either entity or a pharmaceutically acceptable salt of either entity.
This invention is also directed to methods for treating diabetes, obesity, hyperglycemia, frailty associated with obesity or frailty associated with aging or for enhancing the quality of sleep in a mammal comprising administering to said mammal in need of such treatment a therapeutically effective amount of a xcex23 adrenergic agonist and a growth hormone secretagogue or growth hormone.
In the methods set forth in the preceding paragraph, an especially preferred method, designated Method A, is wherein said xcex23 adrenergic agonist is a compound of formula I above, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
A preferred method within Method A, designated Method B, is wherein said xcex23 adrenergic agonist is (4-(2-(2-(6-aminopyridin-3-yl))-2(R)-hydroxyethylamino)ethoxy)phenyl)acetic acid, a prodrug thereof or a pharmaceutically acceptable salt of said xcex23 adrenergic agonist or said prodrug.
A preferred method within Method B, designated Method C, comprises growth hormone.
A preferred method within Method C comprises treating diabetes in a mammal.
Another preferred method within Method C comprises treating hyperglycemia in a mammal.
Another preferred method within Method C comprises treating obesity in a mammal.
Another preferred method within Method C comprises treating frailty associated with obesity in a mammal.
Another preferred method within Method C comprises treating frailty associated with aging in a mammal.
Another preferred method within Method C comprises enhancing the quality of sleep of a mammal.
A preferred method within Method B, designated Method D, is wherein said growth hormone secretagogue is a compound of Formula IV above, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
A preferred method within Method D, designated Method E, is wherein said growth hormone secretagogue is 2-amino-N-(2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide, a prodrug thereof or a pharmaceutically acceptable salt of said growth hormone secretagogue or said prodrug.
A preferred method within Method E comprises treating diabetes in a mammal.
Another preferred method within Method E comprises treating hyperglycemia in a mammal.
Another preferred method within Method E comprises treating obesity in a mammal.
Another preferred method within Method E comprises treating frailty associated with obesity in a mammal.
Another preferred method within Method E comprises treating frailty associated with aging in a mammal.
Another preferred method within Method E comprises enhancing the quality of sleep of a mammal.
Yet another preferred method within Method D, designated Method F, is wherein said growth hormone secretagogue is 2-amino-N-(1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-yl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide, a prodrug thereof or a pharmaceutically acceptable salt of said growth hormone secretagogue or said prodrug.
A preferred method within Method F comprises treating diabetes in a mammal.
Another preferred method within Method F comprises treating hyperglycemia in a mammal.
Another preferred method within Method F comprises treating obesity in a mammal.
Another preferred method within Method F comprises treating frailty associated with obesity in a mammal.
Another preferred method within Method F comprises treating frailty associated with aging in a mammal.
Another preferred method within Method F comprises enhancing the quality of sleep of a mammal.
Yet another preferred method within Method D, designated Method G, is wherein said growth hormone secretagogue is 2-amino-N-{1(R)-benzyloxymethyl-2-[1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide, a prodrug thereof or a pharmaceutically acceptable salt of said growth hormone secretagogue or said prodrug.
A preferred method within Method G comprises treating diabetes in a mammal.
Another preferred method within Method G comprises treating hyperglycemia in a mammal.
Another preferred method within Method G comprises treating obesity in a mammal.
Another preferred method within Method G comprises treating frailty associated with obesity in a mammal.
Another preferred method within Method G comprises treating frailty associated with aging in a mammal.
Another preferred method within Method G comprises enhancing the quality of sleep of a mammal.
This invention is also directed to methods of increasing the content of lean meat in edible animals comprising administering to an edible animal an amount of a xcex23 adrenergic agonist and a growth hormone secretagogue or growth hormone.
In the methods set forth in the immediately preceding paragraph, a preferred method, designated Method H, is wherein said xcex23 adrenergic agonist is a compound of Formula I above, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
A preferred method within Method H, designated Method I, is wherein said xcex23 adrenergic agonist is (4-(2-(2-(6-aminopyridin-3-yl)-2(R)-hydroxyethylamino)ethoxy)phenyl)acetic acid, a prodrug thereof or a pharmaceutically acceptable salt of said xcex23 adrenergic agonist or said prodrug.
A preferred method within Method I comprises growth hormone.
Another preferred method within Method I, designated Method J, is wherein said growth hormone secretagogue is a compound of Formula IV above, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
A preferred method within Method J is wherein said growth hormone secretagogue is 2-amino-N-(2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide, a prodrug thereof or a pharmaceutically acceptable salt of said growth hormone secretagogue or said prodrug.
Another preferred method within Method J is wherein said growth hormone secretagogue is 2-amino-N-(1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-yl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred method within Method J is wherein said growth hormone secretagogue is 2-amino-N-{1(R)-benzyloxymethyl-2-[1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
This invention is also directed to kits comprising:
a. an amount of a xcex23 adrenergic agonist, a prodrug thereof or a pharmaceutically acceptable salt of said xcex23 adrenergic agonist or said prodrug in a first unit dosage form;
b. an amount of a growth hormone secretagogue or growth hormone, a prodrug thereof or a pharmaceutically acceptable salt of said growth hormone secretagogue or said prodrug in a second unit dosage form; and
c. a container.
In the kits set forth in the immediately preceding paragraph, a preferred kit, designated Kit A, is wherein said xcex23 adrenergic agonist is a compound of Formula I above, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
A preferred kit within Kit A, designated Kit B, is wherein said xcex23 adrenergic agonist is (4-(2-(2-(6-aminopyridin-3-yl)-2(R)-hydroxyethylamino)ethoxy)phenyl)acetic acid, a prodrug thereof or a pharmaceutically acceptable salt of said xcex23 adrenergic agonist or said prodrug.
A preferred kit within Kit B comprises growth hormone.
Another preferred kit within Kit B, designated Kit C, is wherein said growth hormone secretagogue is a compound of the Formula IV above, a prodrug thereof or a pharmaceutically acceptable salt of said growth hormone secretagogue or said prodrug.
A preferred kit within Kit C is wherein said growth hormone secretagogue is 2-amino-N-(2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide, a prodrug thereof or a pharmaceutically acceptable salt of said growth hormone secretagogue or said prodrug.
Another preferred kit within Kit C is wherein said growth hormone secretagogue is 2-amino-N-(1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-yl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide, a prodrug thereof or a pharmaceutically acceptable salt of said growth hormone secretagogue or said prodrug.
Another preferred kit within Kit C is wherein said growth hormone secretagogue is 2-amino-N-{1(R)-benzyloxymethyl-2-[1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide, a prodrug thereof or a pharmaceutically acceptable salt of said growth hormone secretagogue or said prodrug.
This invention also relates to compositions, methods and kits for treating insulin resistant conditions such as Non-Insulin Dependent Diabetes Mellitus (NIDDM) and reduced glycemic control associated with obesity and aging in a mammal in need thereof which comprises administering to said mammal an effective amount of a xcex23 adrenergic agonist, a prodrug thereof or a pharmaceutically acceptable salt of said xcex23 adrenergic agonist or said prodrug and a growth hormone secretagogue, a prodrug thereof or a pharmaceutically acceptable salt of said growth hormone secretagogue or said prodrug. The compounds of Formula I are particularly preferred xcex23 adrenergic agonists. The compounds of Formula IV are particularly preferred growth hormone secretagogues.
This invention also provides a method of using a composition comprising a xcex23 adrenergic agonist and a growth hormone secretagogue or growth hormone to treat diabetes, obesity, hyperglycemia, frailty associated with obesity or frailty associated with aging or for enhancing the quality of sleep in a mammal comprising administering to said mammal in need of such treatment a therapeutically effective amount of said composition.
Included within the scope of the present invention is a method of using a combination of this invention, i.e., a xcex23 adrenergic agonist and a growth hormone secretagogue or growth hormone, for enhancing and improving the quality of sleep. The combination is useful in enhancing or improving sleep quality as well as preventing and treating sleep disorders and disturbances in a mammal. In addition, the use of the combination of this invention increases sleep efficiency and augments sleep maintenance. The combination of this invention may further be used in a method for preventing and treating sleep disorders and sleep disturbances in a mammal. The present invention further provides a pharmaceutical composition for enhancing or improving sleep quality and increasing sleep efficiency and sleep maintenance.
The present method of using a combination of this invention further provides the following: an increase in the value which is calculated from the time that a subject sleeps divided by the time that a subject is attempting to sleep; a decrease in sleep latency, i.e., the time it takes to fall asleep; a decrease in difficulties in falling asleep; a decrease in the number of awakenings during sleep; a decrease in nocturnal arousals; a decrease in the time spent awake following the initial onset of sleep; an increase in the total amount of sleep; and increase in the amount and percentage of rapid eye movement (REM) sleep; an increase in the duration and occurrence of REM sleep; a reduction in the fragmentation of REM sleep; an increase in the amount and percentage of stage 2 sleep; an enhancement of EEG-delta activity during sleep; a decrease in the number of awakenings; a decrease in nocturnal arousals, especially early morning awakenings; an increase in daytime alertness; an increased satisfaction with the intensity of sleep; and increased sleep maintenance. Secondary outcomes which may be provided by the present invention include enhanced cognitive function and increased memory retention.
The present invention is further useful for the prevention of sleep disorders and sleep disturbances including: sleep problems associated with insomnia, hypersomnia, sleep apnea, narcolepsy, nocturnal dysomnias, night terror, insomnias associated with depression or with emotional/mood disorders, as well as sleep walking and enuresis, as well as sleep disorders which accompany aging, sleep disorders associated with obesity, conditions associated with circadian rhythmicity, mental and physical disorders associated with travel across time zones and with rotating shift-work schedules, or syndromes such as fibromyalgia which are manifested by non-restorative sleep and muscle pain or sleep apnea which is associated with respiratory disturbances during sleep.
The present invention has several advantagous veterinary features. For the pet owner or veterinarian who wishes to increase leanness and trim unwanted fat from pet animals, the present invention provides the means by which this can be accomplished. For poultry, cattle and swine raisers, using the method of the present invention yields leaner animals which command higher prices from the meat industry.